The impact of the management strategies for patients with subclinical hypothyroidism on long-term clinical outcomes: An umbrella review

Aim This umbrella review summarises and compares synthesised evidence on the impact of subclinical hypothyroidism and its management on long-term clinical outcomes. Methods We conducted comprehensive searches on MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, JBI Evidence Synthesis, the PROSPERO register, Epistemonikos Database and PDQ Evidence from inception to February and July 2021 using keywords on subclinical hypothyroidism, treatment with levothyroxine, monitoring and primary outcomes (all-cause mortality, cardiovascular events, stroke, frailty fractures and quality of life). Only systematic reviews and meta-analyses on adult patient populations were considered. Study selection, data extraction and quality appraisal using AMSTAR-2 were done independently by two reviewers and discrepancies were resolved through discussion. Overlap across the selected reviews was also assessed, followed by a narrative synthesis of findings. Results A total of 763 studies were identified from literature searches; 20 reviews met inclusion criteria. Methodological quality ratings were high (n = 8), moderate (n = 7), and low (n = 5), but no reviews were excluded on this basis. Though there was slight overlap across all reviews, some pairwise comparisons had high corrected covered area scores. Compared to euthyroidism, untreated subclinical hypothyroidism was associated with a higher risk of cardiovascular events or death if Thyroid Stimulating Hormone was above 10mIU/L at baseline. Treatment was associated with a lower risk of death from all causes for patients younger than 70 years and possibly better cognitive and quality of life scores than untreated individuals. Evidence on the risk of strokes and fractures was inconclusive. Conclusion In the long term, treatment of subclinical hypothyroidism may be beneficial for some patient groups. However, the findings of this review are negatively impacted by the relative sparseness and poor quality of available evidence. Additional large and adequately powered studies are needed to investigate this topic further. Systematic review registration PROSPERO (CRD42021235172)

differ in their recommendations for treatment thresholds and exclusions [14,16]; these differences can be directly ascribed to inconsistencies in the existing evidence base.
Based on a systematic review by Feller et al. [17], a clinical guideline panel found no evidence to recommend thyroid hormone replacement for SCH patients, except for those with TSH levels above 20mIU/L and women that are pregnant or trying to conceive [14]. For the outcomes they considered, for example, quality of life, cognitive function and cardiovascular events, the panel found no vital difference between treated and untreated groups, irrespective of patient age. Moreover, they noted the issue of practicality regarding medication-patients require long-term treatment and follow-up and even risk developing hyperthyroidism in case of overuse [14]. In contrast, the latest NICE guidance recommendation is for physicians to consider treating adults with TSH of � 10 mIU/L to improve SCH patient outcomes [16]. The reviewing committee found little evidence on SCH treatment but emphasised that additional factors-such as the presence of symptoms-should be considered, over and above TSH levels [13].
Therefore, an umbrella review was performed to collate and compare existing literature on the long-term effects of SCH treatment and follow-up with no medication. Umbrella reviewsalso called overviews, meta-reviews or reviews of reviews [18]-are ideally suited to exploring discrepancies in the literature by allowing for a broader scope of inquiry than a typical systematic review [18,19]. The review questions of interest were: (i) what is the impact of levothyroxine treatment on patient outcomes in subclinical hypothyroidism? and (ii) what is the impact of monitoring without treatment on clinical outcomes for patients with subclinical hypothyroidism? Rather than restrict the focus of this overview to a direct comparison of these management strategies, we sought also to identify what is known for either option.

Methods
To a large extent, umbrella reviews are conducted similarly to typical systematic reviews. However, the critical difference between these methods is that the former use existing systematic reviews and meta-analyses as the units of synthesis [18]. These will subsequently be referred to as 'primary reviews' in this paper, in contrast to 'primary studies', the empirical studies included in the systematic reviews. The protocol for this overview was registered on PROS-PERO (CRD42021235172) and the methods followed have previously been described in detail [20]; there were no deviations from the registered protocol. The reporting of this overview follows a checklist developed for overviews of systematic reviews based on recommendations from existing guidelines [21].

Eligibility criteria
The following eligibility criteria were considered to determine inclusion in this umbrella review. Only systematic reviews and meta-analyses on SCH, either in part or as a whole, were considered, irrespective of whether the primary review included randomised trials or observational studies. Generally, all primary reviews had to report on the clinical outcomes of adult patients (>18 years old) with SCH, regardless of the diagnostic thresholds that were initially applied, for example, reference ranges for TSH and thyroid hormones. Patients with overt hypothyroidism were excluded, as were children and pregnant women, whose thyroid hormone requirements differ from the rest of the population.
The two eligible interventions were: (i) treatment with levothyroxine, and (ii) patient follow-up without medication. Another essential requirement was that the treatment status of patients was reported in the systematic reviews, such that it would be possible to distinguish between treated and untreated groups. There were no additional restrictions on study comparators and settings.
The primary outcomes of interest were all-cause mortality, defined as the death of patients with SCH, irrespective of the cause, at least 12 months from baseline or the start of follow-up; cardio-and cerebrovascular outcomes such as heart failure, arrhythmias, stroke, peripheral vascular disease, coronary heart disease; quality of life as measured using suitable instruments (or otherwise described as 'symptoms' particularly in older publications); and, frailty fractures, defined as fractures resulting from low-impact trauma, usually due to pre-existing disease. Other long-term clinical outcomes reported in the included systematic reviews, for example, cognitive function, were considered secondary outcomes.

Study selection
References retrieved from the searches were imported into Covidence (www.covidence.org/) and initially screened in duplicate for eligibility by title and abstract. After that, the full texts of selected primary reviews were obtained and read independently by pairs of reviewers who assessed each paper against the selection criteria. When needed, primary review authors were contacted to provide additional information.

Data extraction
A data extraction form was developed on Covidence and piloted by two reviewers. This form was used to extract information on citation details, primary study selection criteria, search parameters, selection and quality assessment methods and primary review findings relating to the outcomes of interest for this umbrella review. Where provided, effect estimates were extracted alongside their 95% confidence intervals and the treatment status of the assessed group(s). This process was done by two reviewers working independently, and discrepancies in the extracted data were resolved through discussion to reach a consensus.

Quality appraisal
The quality of the selected systematic reviews was independently assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR-2) tool [22], an instrument with 16 questions on the methodological quality of systematic reviews. These questions include whether a comprehensive literature search was conducted, justification for excluding studies, and risk of bias assessments for included studies (S2 Appendix). Overall ratings and their meanings are shown in Table 1. AMSTAR-2 was chosen over the risk of bias in systematic reviews (ROBIS) tool [23] because while both assess strongly related aspects (methodological quality vs risk of bias), the former is advantageous for inter-rater reliability and usability [24][25][26]. Disagreements between the reviewers were similarly resolved through discussion. It has been suggested that GRADE criteria can be applied to systematic reviews [27]. However, this approach was initially designed for empirical studies, hence the paucity of relevant guidance on how best to achieve this [18,28]. Therefore, we did not perform any secondary GRADE assessments on the included primary reviews but extracted any reported quality ratings.

Assessing overlap
One of the unique challenges in conducting an umbrella review is overlap-the inclusion of the same primary study or trial in more than one selected systematic review or meta-analysis [29,30]. Any subsequent synthesis of more than one of these primary reviews would result in 'double-counting' and biased findings because the contribution of a subset of the data would have been multiplied by some factor [30,31]. The proposed methods for dealing with overlap are: (i) selecting only the most recent systematic review or the one with the largest number of studies, (ii) selecting only the primary review of the highest quality, or (iii) including all primary reviews but evaluating the amount of overlap [18,30,31].
To assess overlap between the included primary reviews, we calculated the corrected covered area (CCA) using the formula described by Pieper et al. [29]: where N-number of included primary studies in selected reviews r-number of index publications c-number of included primary reviews A matrix of the included systematic reviews and their primary studies was created to identify the numerators and denominators shown above. CCA is interpreted in banded thresholds: 5% or less indicates slight overlap, 6% to 10% shows moderate overlap, 11% to 15% for high overlap and values greater than 15% indicate very high overlap [29].

Synthesis of results
A narrative synthesis of results was performed due to high levels of study overlap and considerable heterogeneity in primary review inclusion criteria and reported outcomes. Summaries of the included primary reviews are presented below in tabular form alongside corresponding effect estimates such as odds and hazard ratios (where reported). Of note, no further re-analysis of empirical study data was performed, as previously stated in the umbrella review protocol [20]. The extracted data were grouped according to the clinical outcome of interest, regardless of the degree of overlap among sets of studies. Moreover, because there is currently no agreedupon solution for the issue of low-quality systematic reviews in overviews [18,26], all selected papers were included in the narrative synthesis.

Results
In total, 763 records were retrieved from the initial and updated searches. After screening by title, abstract and full-text, 20 syntheses were selected for inclusion in this umbrella review. Notably, two otherwise eligible primary reviews were excluded based on all their included studies having been used in later publications by the same authors [32,33]. Authors were unable to provide further information for two other publications [34,35]. One item of grey literature, a systematic evidence review commissioned by a government agency for healthcare research, was included [36]. A list of the systematic reviews that were excluded after reading full texts is provided in S3 Appendix. The PRISMA flowchart [37] showing the stages of study selection is presented in Fig 1. The characteristics of the selected primary reviews are shown in Table 2. Of the 20 included syntheses, four were systematic reviews [36,[38][39][40], five were published as combined systematic reviews and meta-analyses [17,[41][42][43][44], six were labelled meta-analyses [45][46][47][48][49][50], and five were individual participant data analyses [51][52][53][54][55]. The majority were published earlier than the TRUST trial [15], with only seven primary reviews published during or after 2017 [17, 38, 41-43, 50, 51]. Most of the primary reviews synthesised observational data, although three papers only included RCTs [17,36,40]. Generally, SCH was defined using similar TSH thresholds (> 4.5 mIU/L) and normal T4, but some studies subdivided this further into degrees of SCH or TSH elevation e.g., mild vs moderate ( Table 2).

PLOS ONE
Management strategies for patients with subclinical hypothyroidism: An umbrella review Treatment was found to benefit SCH patients younger than 65 years; all-cause mortality decreased by 50%, and cardiovascular mortality decreased by 46%. However, the same did not apply to patients older than 65 years. There was also no overall benefit of treatment on mortality.
High (Continued ) The overall incidence of IHD and mortality was not significantly higher for patients with SCH, but IHD prevalence was found to be significantly elevated for patients younger than 65 years. There was a significantly higher risk of CHD and cardiovascular mortality for SCH patients younger than 65 years, but the same effect was not observed for patients older than 80 years. A slightly higher risk of AF and HF was also associated with SCH.

Moderate (Continued )
Coverage of the primary outcomes was good, given that all the outcomes of interest were reported in at least two publications. However, it is crucial to note that most relevant results were obtained via subgroup or sensitivity analyses in the primary reviews. As such, they were not necessarily representative of the overall findings shown in Table 2.

All-cause mortality
Seven publications reported findings on all-cause mortality; of these, three primary reviews compared rates between treated and untreated patients [38,39,42], three compared untreated and euthyroid individuals [43,46,48], and one compared both treated and untreated SCH groups with euthyroid participants [50]. There was no statistically significant difference in the overall numbers of deaths from all causes for patients with SCH between those who were and were not on treatment (Table 3).
Taking age into account, lower estimates of all-cause mortality were reported for patients younger than 70 years on treatment (RR 0.50, 95% CI 0.29 to 0.85 [42]; HR 0.36, 95% CI 0.19 to 0.66 [38,39]). However, these estimates were based on one study in Rugge et al. [39], and another paper rated the same evidence as being of very low certainty [38]. On the other hand, older patient groups demonstrated no significant association between levothyroxine treatment and all-cause mortality (Table 3). Only one of four comparisons of all-cause mortality between untreated and euthyroid study participants was statistically significant (HR 1.48, 95% CI 1.29 to 1.70) [50]. The same review found that death was more likely among SCH patients on treatment than in euthyroid persons (HR 1.48, 95% CI 1.14 to 1.94) [50]. However, the population of interest for this review all had heart failure, thereby limiting the generalisability of these findings to other SCH patients.

Cardiovascular outcomes
Cardiovascular outcomes were the most extensively reported outcomes of interest across the included reviews (n = 13) as shown in Table 4. No difference was found in the number of incident atrial fibrillation events between untreated persons and euthyroid controls, irrespective of age and TSH level [51]. Similarly, the difference between treated and untreated SCH patients was not statistically significant, though notably, the evidence was rated as being of very low to moderate certainty [38].
Compared to euthyroidism, untreated SCH was significantly associated with a higher likelihood of CHD and heart failure if patients had TSH levels above 10mIU/L (HR 2.17, 95% CI 1.19 to 3.93) [55], (HR 2.37, 95% CI 1.59 to 3.54) [54] or were thyroid peroxidase antibodynegative (HR 1.25, 95% CI 1.06 to 1.47); HR (3.76, 95% CI 1.77 to 8.01) [53]. It was also reported that untreated SCH was associated with higher odds of ischaemic heart disease (OR 1.58, 95% CI 1.07 to 2.35) [46] and a higher risk of developing coronary heart disease during follow-up (RR 1.188, 95% CI 1.024 to 1.379) [48] than euthyroid participants. However, one primary review found that incident CHD was not associated with untreated SCH [43]-this difference may have resulted from the reviewers' decision to restrict the inclusion of primary studies based on quality appraisal scores. SCH patients receiving treatment and younger than 70 years were significantly less likely to develop IHD than untreated individuals (HR 0.61, 95% CI 0.39 to 0.95) [38]. However, these findings were based on a single empirical study in both primary reviews, in which it was reported that the GRADE rating for this evidence was very low. A similar association was not found for patients older than 70 years nor subgroups based on sex [38]. We distinguished between all-cause mortality and cardiovascular mortality (n = 8), which primary review authors defined as deaths arising from cardiovascular diseases ( Table 5). Considering treated vs untreated SCH, an association between treatment and cardiovascular death was found only for adult patients younger than 65-70 years [38,39,42]. Stratifying the results by sex did not yield statistically significant findings. In addition, whereas the risk of cardiovascular mortality was found to be higher for untreated SCH patients compared to euthyroid controls in four primary reviews [48,50,53,55], Sun et al. [43] reported a lower nonsignificant estimate (RR 0.86, 95% CI 0.56 to 1.32) [43]. A possible reason for this difference, despite very high overlap between pairs of these primary reviews, could be discrepancies in the determination of treatment status. Furthermore, Sun et al. [43] rated the quality of evidence for cardiovascular mortality in their primary review as low because of high heterogeneity.
Only one primary review considered the relationship between thyroid peroxidase antibody status and cardiovascular mortality. Collet et al. [53] found that untreated thyroid antibodynegative SCH was significantly associated with cardiovascular mortality (HR 1.34 95% CI 1.07 to 1.69), but the same did not apply for antibody-positive SCH (HR 1.28, 95% CI 0.94 to 1.72) [53], except for patients that also had TSH levels above 10mIU/L (HR 1.92, 95% CI 1.09 to 3.36) [53]. Finally, compared to euthyroid controls, death and hospitalisation due to cardiovascular causes were more likely to occur among treated SCH patients with heart failure [50].

Stroke
There were no direct comparisons of the risk of stroke between treated and untreated patients with SCH. One primary review compared untreated individuals with SCH with euthyroid controls, and no significant difference was found in either the incidence of strokes or deaths arising from strokes [52]. Dhital et al. [41] found that functional outcomes for untreated SCH (based on the modified Rankin scale) were twice as likely to be better than those for euthyroid controls 1 and 3 months after acute ischemic stroke (Table 6).

Fractures
No primary reviews that compared the risk or likelihood of fractures between euthyroid individuals and SCH patients that did or did not receive treatment found a significant difference (Table 7). This result was similar across various types of fractures, for example, hip fractures (HR 1.02, 95% CI 0.87 to 1.19 [45]; HR 1.10, 95% CI 0.81 to 1.50 [44]) and spine fracture (HR 1.16, 95% CI 0.66 to 2.04) [45].

Quality of life and presence of symptoms
For the 5 studies that explicitly reported quality of life outcomes, no statistically significant differences were found between patients who did and did not receive treatment for SCH (Table 8). Similarly, thyroid-related symptoms, fatigue, mental and general well-being scores were not significantly associated with treatment status. However, Helfand [36] reported that specific subgroups-patients with TSH values greater than 10 mIU/L and those with a history of Graves' disease seemed to benefit from treatment. Graves' disease is an autoimmune thyroid disorder treated with antithyroid medication, radiotherapy or surgery [56]. Nonetheless, it is noted that the single study that this finding was based upon was a small trial of 33 participants, all of whom had previously treated Graves' disease [36].

Secondary outcomes
Some of the included papers (n = 4) reported on cognitive function (Table 9), which was assessed using various tools such as the Letter-Digit Coding Test and Mini-Mental State Examination. All of the primary reviews found no significant difference in cognitive function between treated and untreated groups [17,38,39] except Villar et al. [40]. However, this result was based on only one included study with an unclear risk of bias assessment.

Overlap
The extent of overlap in this umbrella review is shown in Fig 2, an intersection heatmap of the calculated CCA between pairs of the 20 included primary reviews. As shown, only one of the included evidence syntheses [41] had a unique set of primary publications compared to all the other primary reviews. Overall, excluding the diagonal, the pairwise comparisons showed slight (66.7%), moderate (10%), high (2.6%) and very high (20.8%) overlap. However, it should be noted that these values were obtained with no consideration of the specific outcomes   reported in each of the primary reviews and therefore require cautious interpretation. That is because, although calculating CCA involved mapping all the primary studies included in each publication, not all provided findings relevant to this umbrella review. The fundamental reason for this complexity is that we were only interested in estimates reported with the participants' corresponding treatment status. On balance, CCA for the entire overview was calculated to be 5.12%, the higher limit for slight overlap [29].

Discussion
This umbrella review on the impact of the management of SCH on clinical outcomes covers evidence from 20 selected systematic reviews and meta-analyses of RCTs and observational studies. Across the outcomes of interest, the synthesised literature found can be summarised as follows. We found that the treatment of SCH may be associated with a reduced likelihood of death from all causes for patients under 70 years old. On the other hand, the relationship between SCH treatment status and the risk of death compared to the euthyroid population remains unclear. Increased risk of all-cause mortality for untreated SCH was reported in only one primary review [50], for which inclusion was restricted to patients with comorbid heart failure.
We also found that compared to euthyroidism, untreated SCH patients with very high TSH (>10mIU/L) may be at greater risk of cardiovascular events and death from cardiovascular disease [54,55]. The same effects were observed for thyroid peroxidase antibody-negative patients [53]. Even so, there was discordance in findings between the primary reviews; whereas seven primary reviews reported a higher risk of CHD and cardiovascular mortality for untreated SCH patients than euthyroid persons [46-48, 50, 53-55], one primary review did not [43]. We rated the latter as having more than one non-critical weakness according to the AMSTAR-2 checklist; the others were either 'high' or 'moderate' in overall confidence in their results (Table 10). A high degree of overlap was calculated between the studies reporting cardiovascular outcomes, as high as 38%. Therefore, it was not easy to ascertain the precise source of the difference in results.
It was not possible to investigate the impact of treatment on the risk of stroke because the only available comparisons were of untreated SCH and euthyroidism. The finding that untreated patients had better functional outcomes one month following stroke was reported only in one low-quality study [41] and is, therefore, inconclusive. In a similar vein, there was insufficient evidence of the impact of treatment or no treatment of SCH on fracture risk. Overall confidence in the results of three out of the four primary reviews [38,44,45] was rated as 'high' or 'moderate'. However, none of the effect estimates was statistically significant, so it is also not possible to make conclusions on this relationship based on the quantity of evidence.  Reported findings on quality of life and the presence of symptoms between treated and untreated SCH patients were mainly of no statistical significance. As such, we cannot definitively state whether levothyroxine treatment improves or worsens these outcomes. Nonetheless, medication potentially benefits two patient groups-patients with severe SCH from the start and those that previously received treatment for autoimmune hyperthyroidism/Graves' disease [36].
The secondary outcome reported in the included primary reviews, cognitive function, was only compared between treated and untreated SCH patients. Given that the majority of findings were similar, it may be said that among patients with SCH, levothyroxine may have no significant impact on cognitive function, notwithstanding the type of assessment tool used [17,[38][39][40]. Crucially, however, two points must be emphasised. First, that the amount of evidence in favour of this statement is notably low, considering that few primary reviews that reported on cognitive function. Second, that only the primary outcomes were included in the literature searches, so the findings in this review cannot accurately reflect the body of evidence regarding the relationship between SCH and cognitive function.
With reference to the number of primary reviews, the volume of evidence was discernibly skewed in favour of cardiovascular outcomes (n = 13) rather than all-cause mortality (n = 7), stroke (n = 2), fractures (n = 4), quality of life (n = 5) and cognitive function (n = 4). This observation can be explained as having arisen from the umbrella review selection process, but the relatively broad inclusion criteria make it less probable. Instead, two alternatives are suggested; either that less research has been performed on the other clinical outcomes of interest or that the evidence may not have already been synthesised due to high between-study heterogeneity, for example, in outcome definitions and measurements. Additional factors, such as the comparative ease of measuring certain outcomes over others, may also influence which types of studies are performed. However, it is not possible to conclusively account for this asymmetry of evidence from this overview alone.
Generally, it cannot be ignored that most of our findings were based on empirical studies of poor quality, as reported by the authors of the primary reviews. Equally important were the critical flaws we found in the methodological quality of five of the selected primary reviews [36,41,[48][49][50] consequently rated as 'low' in overall confidence in their results. Upon inspection, there was no clear boundary of review quality based on the type of empirical research that was initially selected. For example, all the syntheses that included only RCTs did not consistently get higher AMSTAR-2 ratings than those of only observational studies. As such, it can be argued that cohort studies have an essential role in filling the gap left by insufficient randomised trials on this topic.
It should be noted that there was a tendency for papers with the lowest ratings on the AMSTAR-2 checklist to have little overlap of empirical studies with other higher-rated primary reviews. This could be explained by differences in the types of outcomes reported in these syntheses; for instance, one would expect minimal overlap between fractures and cardiovascular mortality. Collectively, the reviews included in this overview had slight overlap, but as Hennesy and Johnson [31] contend, such an observation can be attributed to the breadth of the literature. This is especially true if only a small set of identical studies is shared across the included syntheses, or the overlap is highly outcome-dependent [31]. In these cases, the overall CCA would obscure the true level of overlap.

Strengths and limitations
To the authors' knowledge, this is the first umbrella review on this topic. This overview was conducted in a systematic manner and comprehensive searches were performed to identify the synthesised literature on the impact of the management of SCH on long-term clinical outcomes. The database searches-including grey literature, to minimise the effects of publication bias [57]-were updated in the course of the review. Screening, data extraction and quality appraisal were all done in duplicate. Furthermore, the intended aim of the umbrella review to compare the synthesised literature on this topic was achieved, even though a secondary metaanalysis was not feasible.
Nonetheless, it is crucial to consider the limitations of this review which relied exclusively on the availability, methods and quality of existing systematic reviews and meta-analyses. Of note, it was not possible to re-analyse and pool all primary review findings due to the variety of selection criteria and outcome definitions. Combining the findings of the included reviews in spite of these differences-and potential confounders-would result in biased and misleading inferences [58].
Also, an inherent limitation of the umbrella review methodology is the limited capacity to conduct detailed evaluations of empirical studies when dealing with synthesised literature. This was particularly challenging when evaluating overlap across the included reviews, as it may have been influenced by factors such as study scope and eligibility criteria. On the other hand, because this type of review was performed, it was possible to examine a wide variety of outcomes for SCH and treatment status within our specific resource constraints. The comprehensive nature of umbrella reviews has been recommended for controversial topics [19]. Furthermore, in this overview, we included IPD meta-analyses, which have been described as beneficial for analysing long-term patient outcomes [59].
Another limitation was scope mismatch between the umbrella review and the included primary reviews, for example, in cases where a selected systematic review included patients with subclinical hypo-and hyperthyroidism. This problem is commonly encountered in overviews [18], and we opted to include such papers for two key reasons. First, a preliminary literature search yielded few results with precisely the same research questions. Second, for an unresolved topic such as this, it was anticipated that the exclusion of these reviews would severely restrict this synthesis by omitting potentially relevant findings. Therefore, to limit this type of bias, inclusion in the umbrella review was based on the availability of results for which treatment status was explicitly stated.
It was also not possible to calculate overlap for the included primary reviews subdivided by their reported outcomes because most included both treated and untreated SCH patients. Consequently, assessing overlap in this way would require a detailed inspection of all their primary studies to identify the exact data sources for the respective subgroup analyses. These activities were considered to be burdensome and beyond the scope of this umbrella review, given that systematic reviews and meta-analyses were the principal units of analysis. Even so, to visualise overlap, we created a citation matrix and presented the results of the pairwise calculations, most of which were in the 'slight' band.

Conclusion
Through this umbrella review, we systematically gathered the existing synthesised literature on the impact of the management of subclinical hypothyroidism on clinical outcomes. Our findings seem to indicate that treatment may be beneficial for SCH patients younger than 70 years due to the higher risk of all-cause mortality and cardiovascular events. In addition, untreated SCH patients with TSH levels above 10mIU/L may be at higher risk of developing cardiovascular diseases than the euthyroid population. However, more robust evidence is needed on stroke, fractures, quality of life and cognitive function in SCH. The main challenge in investigating long-term outcomes is the need for large, adequately powered and timed randomised trials. This overview further highlights this need, given that majority of the significant findings were based on very few empirical studies often deemed to be of poor quality by the primary reviewers. Future work in observational studies may also be instrumental in strengthening the evidence base.